Vitamin D and MS. Gavin Giovannoni

Transcription

1 Vitamin D and MS Gavin Giovannoni

2 Latitude

3 This article was published in McAlpine s Multiple Sclerosis 4 th edition. Compston A. ed. London Churchill Livingstone Elsevier 2006;55 Fig 1.33 Copyright Elsevier (2007) Geographical Distribution of MS First study of geographical distribution of MS prevalence by Davenport Key finding: Geographical variation in MS prevalence, implying population (genetic) and environmental contributions to MS risk Davenport CB. In: Association for Research in Nervous and Medical Conditions (ARNMD), vol 2. New York: Hoeber, 1921;pp8 19.

4 Prevalence of MS in the USA. Kurtzke et al, 1980

5 . Koch-Henriksen and Sorenson, 2010

6 MS-related hospital admissions England Ramagopalan et al, 2011

7 Relationship of MS prevalence to ultraviolet exposure Ramagopalan et al, 2011

8 UVB and MS prevalence in France MS Prevalence by Department Against UVMED Minimum Department UVMed MIN Orton et al. Neurology Feb 1;76(5):

9 Prevalence of MS in Norway Prevalence data for counties in Norway (/10 5 ): A A Finnmark 1 (2003) >83 B B Troms 1 (2003) >104 C Nordland (1999) 106 D Nord Trøndelag (1999) 164 E Oppland 2 (2002) 190 C F Hordaland (2003) 151 G Oslo 2 (2005) 154 D In Norway, MS prevalence does not rise with increasing latitude, unlike other northern European countries and the USA As expected, measured UV radiation levels decrease with increasing latitude F E G Kampman et al, 2007

10 Fish consumption. Kampman et al, 2007

11 Migration

12 Migration studies Compston & Coles, Lancet 2008.

13 The effect of migration on MS prevalence Gale, 1995

14 Prevention

15 vd supplementation

16 Vitamin D and MS Munger et al, 2004

17 Vitamin D and MS Munger et al, 2004

18 vd levels

19 Vitamin D and MS Munger et al, 2006

20 Vitamin D and MS Munger et al, 2006

21 When to supplement?

22 Vitamin D and MS- Month of Birth Role of light exposure in MS supported by month of birth effect In northern hemisphere, significantly more people with MS are born in May (less light during pregnancy) than November (more light during pregnancy) Birth month effect is inverse in the southern hemisphere Willer et al, 2005

23

24

25

26 Familial risk Compston & Coles, Lancet 2008.

27

28 Ramagopalan et al. PLoS Genet Feb;5(2):e

29 Thymic Education Hypothesis Disanto et al. JAMA Neurol Apr;70(4):527-8.

30 Genome-wide vitamin D receptor mapping using ChIP-seq in Lymphoblastoid Cell Lines Ramagopalan et al, 2010

31 Enrichment for genes associated to autoimmune disease and cancer Ramagopalan et al, 2010

32 Can vd be used as a MS disease modifying therapy?

33 static protective factors protective HLA haplotypes Low risk Prevention dynamic protective factors Very low risk Disease Modification Favourable disease-modifying factors At risk High Risk RIS CIS MS static risk factors dynamic risk factors Unfavourable disease-modifying factors family history genetics sex month of birth place of birth 1. Declining Physiology peripheral immunological endophenotype 2. Biological disease threshold CNS endophenotype 3. Asymptomatic disease RIS (abnormal MRI and/or evoked potentials) 4. Clinical disease a. Clinically isolated syndrome (CIS) b. Relapsing MS c. Relapsing secondary progressive MS d. Non-relapsing secondary progressive MS 1 age place of residence outdoor activity / sun exposure / sun screen diet / vitamin D supplements age of exposure to EBV smoking Peripheral immunological changes T-regs (), NK cells, CD8 () CNS changes (OCBs and microscopic pathology) MRI / evoked potentials changes 4b 2 2 Clinical disease 4c 4d 2 In utero childhood Adolescence / early adulthood adulthood a

34 Vitamin D as an early predictor of MS activity and progression Ascherio JAMA Neurol Mar;71(3):

35 Vitamin D as an early predictor of MS activity and progression Ascherio JAMA Neurol Mar;71(3):

36 Vitamin D as an early predictor of MS activity and progression Ascherio JAMA Neurol Mar;71(3):

37 Multivariate International CIS risk factor study - 25-OH D3 P=0.008 P=0.007 Median Survival: 935 days vs days Conversion to CDMS] HR 95% CI P value 25-OH D Kuhle et al. submitted 2014.

38 Higher 25-OH vd is associated with lower relapse risk Simpson et al. Ann Neurol. 2010;68:

39 vd status predicts new brain MRI activity in MS EPIC is a 5-year longitudinal MS cohort study at the UCSF. 469 subjects annual clinical evaluations, brain MRI, and biomarkers. Each 10ng/ml higher vitamin D level was associated with lower subsequent disability (-0.047; 95% CI = to ; p = 0.037). Mowry et al. ANN NEUROL 2012;72:

40 Chicken or Egg Association? Causation?

41 The effect of the systemic inflammatory response on plasma vitamin 25 (OH) D concentrations adjusted for albumin Vitamin D3 CRP Ghashut et al. PLoS One Mar 25;9(3):e Albumin

42 Hypothesis Hypovitaminosis D3 is a consumptive vitaminopathy. Therefore, the association between low vd levels and disease is due to reverse causation. Association? Causation?

43 Immunomodulatory effects of vd in MS Immune response Correale et al. Brain 2009: 132; Vitamin D3

44 Seasonal Effects

45 Seasonal patterns in optic neuritis and MS: a meta-analysis Jin et al. J Neurol Sci 2000:181;56 64.

46 Seasonal prevalence of MS disease activity Meier et al. Neurology 2010;75:

47 vd and disease activity in MS before and during IFN-beta treatment Løken-Amsrud et al. Neurology Jul 17;79(3):

48 Treatment effects

49 The effect of vitamin D-related interventions on multiple sclerosis relapses: a meta-analysis James et al. Mult Scler Oct;19(12):

50 The effect of vitamin D-related interventions on multiple sclerosis relapses: a meta-analysis James et al. Mult Scler Oct;19(12):

51

52 What dose of vitamin D?

53 Vitamin D Status in Primates and Early Humans Winter 43 o N Latitude 40 0 Old-World Primates Slide adapted from Reinhold Vieth Humans exposing full skin surface to Sunshine s UVB Normal Blood Levels when taking 25 mcg/d 1000 IU/day Northern People Taking 100 mcg/d 4000 IU/day Physiological adult intake Sources, include Cosman, Osteoporosis Int 2000; Fuleihan NEJM 1999; Scharla Osteoporosis Int 1998; Vieth AJCN 1999, 2000

54 Maasai median 25(OH)D = 104 nmol/l = 41 ng/ml 40 ng/ml Slide adapted from Reinhold Vieth Luxwolda et al. British Journal of Nutrition (2012), 108,

55 Osteopaenia: z-scores are lower in MSers Lumbar spine Femoral neck (NS) Dobson et al. Mult Scler Nov;18(11):

56 HES data: risk ratio of fractures in MS Fracture (ICD code*) Observed Expected Rate Ratio (95% confidence interval) P value All fractures ( ) <0.001 Ribs (S22.2-S22.4 ) ( ) Clavicle (S42.0) ( ) <0.001 Humerus (S42.2-S42.4, S42.7) ( ) <0.001 Forearm (S52) ( ) Wrist/Hand (S62) ( ) Pelvis/Lumbar spine (S32.0- S32.8) ( ) <0.001 Tibia/Ankle (S82) ( ) <0.001 Foot (S92) ( ) <0.001 Femur - neck of (S72.0-S72.2) ( ) <0.001 Femur - other (S72.3-S72.8) ( ) <0.001 Femur - unspecified (S72.9) ( ) <0.001 Ramagopalan et al. BMC Neurol Nov 5;12:135.

57 MS prevention Population health-based initiatives Conclusions Targeted high-risk population studies (children and siblings of people with MS) Low vd levels are associated with MS disease activity relapses, disease progression and MRI activity (Gd, T2 and brain volume loss) Possible reverse causation The consumptive hypovitaminosis hypothesis Arguments against consumptive hypovitaminosis hypothesis Worldwide MS epidemiology (latitude, migration, sex ratio, changing incidence, MoB effects) Seasonal variation of MS onset and disease activity Current evidence-base regarding treatment is unconvincing We need large well-controlled randomised clinical trials (easier said than done) We need more basic science to support the causation theory What dose? Evolutionary medicine suggests we need to target a blood plasma level above 100nmol/L What advice? To supplement to achieve a year long blood levels of > nmol/l In the UK we can t rely on diet or sun exposure to achieve these levels EFSA or Vitamin D council recommendations Don t forget bone health as a justification to act now

58 Back-up slide

59 The effect of vitamin D-related interventions on multiple sclerosis relapses: a meta-analysis James et al. Mult Scler Oct;19(12):

60 The conditions for which our human genome was selected offer a reasonable basis for optimal nutrition. Modern humans have existed for 100,000 years Slide adapted from Reinhold Vieth

61 What dose of vd depends where you live? no vd for >6 mo/yr no vd for 1-6 mo/yr vd all year no vd for 1-6 mo/yr no vd for >6 mo/yr Slide adapted from Reinhold Vieth

62 Level of vd supplementation Veith Am J Clin Nutr 1999;69:

63 Cultural changes.

64 Cultural changes

65

66

67

68

69 Do I put my money where my mouth is?

70 Treat-2-Target

71